Natural killer (NK) cells are a key cellular component of the innate immune response and represent one of the mechanisms to activate proinflammatory processes. Although best known for rapid killing of tumor cells and activation during viral infections, NK cells are believed to be important for the proper implantation and maintenance of the developing fetus. NK cells localize specifically to the FRT during the secretory phase of the menstrual cycle. This is somewhat paradoxical since the FRT must keep inflammatory responses tightly controlled to prevent damage to a developing fetus, and high levels of NK cell activity have been associated with an increased rate of spontaneous abortion. However only CD56+, CD16- NK cells are believed to localize to the FRT. How and why this happens is unknown. This application examines three important processes that occur as a part of normal NK cell physiology and their regulation by sex hormones. First, we will define the regulation of NK cell subsets and cell recruitment into tissues by sex hormones. Through the use of chemotaxis assays and in vitro cell culture systems, we will demonstrate the active migration of NK cells into the FRT and determine the mechanism responsible and the extent of regulation by sex hormones. Second, we will ask to what extent sex hormones alter NK cell recognition mechanisms. We will use selected effector-target combinations, activating and blocking antibodies to delineate the active cytotoxic mechanisms used and their regulation by different sex hormones. Third, we will ask if sex hormones program NK cells to differentially secrete cytokines. We will determine the extent to which cells from the blood and FRT secrete different cytokines in response to exogenous stimuli and their regulation by sex hormones. This application aims to address some of these basic questions regarding sex hormone regulation of NK cell function and how specific NK cell subsets are recruited to the FRT. Our studies may provide the basis of knowledge essential for understanding the role of hormones in autoimmune conditions, the prevention of local infection in the genital mucosa, and the management of sexually transmitted diseases.